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Principal Investigator: Amit Praful Khandhar
Organization: HDT BIO CORPORATION
Fiscal Year: 2021
Award: $399,285
Funding agency: National Cancer Institute
PROJECT SUMMARY/ABSTRACT
Effective targeted treatments are needed to improve survival of patients with late stage ovarian
and other solid tumor cancers of epithelial origin. Epithelial cancers are characterized by an
overexpression of tumor tight junctions, specifically the cell adhesion protein desmoglein-2
(DSG2). Unlike in normal epithelial cells, epithelial cancer cells are characterized by abnormal
expression of DSG2, displaying the protein three-dimensionally and outside intercellular
junctions; as a result, DSG2 is an attractive tumor-specific protein for targeted therapies. We
have developed a DSG2-targeting protein called the “junction opener conjugatable to x”,
or JOC-x. A key feature of JOC-x, as its name implies, is the ability to conjugate any moiety with
functional groups to the engineered free sulfhydryl group on JOC-x. In this phase I SBIR, we will
covalently link JOC-x to HDT Bio Corp’s patent-pending Lipid Iron Oxide Nanoparticle
(LIONTM) formulation. The LION formulation is a multifunctional nanoparticle platform. At its core,
LION consists of the widely used immune potentiating molecule squalene and superparamagnetic
iron oxide (SPIO) nanoparticles that give LION the ability to affect tissue contrast in magnetic
resonance imaging (MRI). By covalently combining JOC-x with LION, we propose to (specific
aim 1) synthesize and thoroughly characterize JOC-LION particles that demonstrate colloidal
stability in plasma and effective binding with DSG2. Moreover, (specific aim 2.1) using a 3T
clinical MRI scanner at the University of Washington, we will evaluate the ability of five
candidate JOC-LION particles to target human DSG2 overexpressing ovarian cancer cells
in a transgenic human DSG2 expressing murine model. Finally, since squalene delivered in
nanoparticles is an effective activator of the innate immune system, we will (specific aim 2.2)
evaluate the potential for induction of anti-tumor activity of candidate JOC-LION particles
make the tumor more accessible, both physically, by opening tight junctions, and immunologically,
by recruiting immune cells in the tumor microenvironment. The ultimate goal of this phase I
proposal is to develop a lead JOC-LION candidate that demonstrates a high degree of selective
accumulation in DSG2 overexpressing epithelial tumors and potentially also provides anti-tumor
activity. In phase II, we will combine our lead JOC-LION candidate with both traditional and novel
cancer therapies to justify clinical product development of our novel tumor junction opening and
imaging nanoparticle technology.
Terms: <3-D><3-Dimensional><3D><Adhesion Molecule><Affect><Anti-Cancer Agents><Antineoplastic Agents><Antineoplastic Drugs><Antineoplastics><Apical><Basal Cell><Binding><Blood Plasma><Body Tissues><Cancer Drug><Cancer Model><Cancer Prognosis><Cancer Treatment><CancerModel><Cancers><Carcinoma><Cell Adhesion Molecule Gene><Cell Adhesion Molecules><Cell Body><Cell Junctions><Cells><Clinical><Disease><Disorder><Drops><Drugs><Engineering><Epithelial><Epithelial Cells><Epithelial cancer><Formulation><Goals><Human><Hydrophobicity><Image><Immune><Immune system><Immunes><Immunochemical Immunologic><Immunocompetent><Immunologic><Immunological><Immunologically><Immunologics><Innate Immune System><Intercellular Junctions><Lead><Legal patent><Link><Lipids><MR Imaging><MR Tomography><MRI><Magnetic Resonance Imaging><Malignant Cell><Malignant Epithelial Neoplasms><Malignant Epithelial Tumors><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Ovarian Neoplasm><Malignant Ovarian Tumor><Malignant Tumor><Malignant Tumor of the Ovary><Malignant neoplasm of ovary><Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance><Medication><Membrane Protein Gene><Membrane Proteins><Membrane-Associated Proteins><Mercaptans><Mercapto Compounds><Mice><Mice Mammals><Modern Man><Molecular Interaction><Murine><Mus><NMR Imaging><NMR Tomography><Names><Neoplastic Disease Chemotherapeutic Agents><Nuclear Magnetic Resonance Imaging><Occluding Junctions><Opsonin><Ovarian><Ovary Cancer><Particle Size><Patents><Patients><Pb element><Penetration><Pharmaceutic Preparations><Pharmaceutical Preparations><Phase><Plasma><Plasma Serum><Proteins><Reticuloendothelial System, Serum, Plasma><SBIR><Selection Criteria><Small Business Innovation Research><Small Business Innovation Research Grant><Solid Neoplasm><Solid Tumor><Squalene><Structure><Sulfhydryl Compounds><Surface><Surface Proteins><Survival Rate><Technology><Therapeutic><Thiols><Tight Junctions><Tissues><Transgenic Organisms><Treatment Efficacy><Tumor-Specific Treatment Agents><Universities><Viral><Visualization><Washington><Zeugmatography><Zonula Occludens><allergic/immunologic body system><allergic/immunologic organ system><anti-cancer drug><anti-cancer therapy><anti-tumor drugs><anticancer agent><anticancer drug><anticancer therapy><antitumor drug><base><cancer cell><cancer microenvironment><cancer therapy><cancer-directed therapy><cell adhesion protein><commercialization><design><designing><desmoglein 2><desmoglein II><desmosomal glycoprotein 2><drug/agent><epithelial carcinoma><functional group><heavy metal Pb><heavy metal lead><imaging><immune competent><improved><innovate><innovation><innovative><intervention efficacy><iron oxide nano particle><iron oxide nanoparticle><lead candidate><malignancy><monolayer><mouse model><multi-modality><multimodality><murine model><nano particle><nano-sized particle><nanoparticle><nanosized particle><neoplasm/cancer><novel><ovarian cancer><overexpress><overexpression><particle><polarized cell><prevent><preventing><product development><recruit><sulfhydryl group><superparamagnetic><superparamagnetism><targeted drug therapy><targeted drug treatments><targeted imaging><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic efficacy><therapy efficacy><three dimensional><transgenic><tumor><tumor microenvironment>